Although NSAIDs are often used for their antiinflammatory, analgesic, and/or antipyretic effects, it is well known that NSAIDs have the potential to cause gastrointestinal (GI) bleeding through a variety of mechanisms related to their topical and systemic effects. The GI bleeding may depend on the length of the treatment and on the particular drug. This problem is important in cases where the therapy must be continued for a long period of time. For example, osteoarthritis and rheumatoid arthritis in the elderly is often treated with long-term NSAID therapy, as chronic treatment is needed to control pain and inflammation and to improve quality of life.
Additionally it is well known that because of their side-effects on the GI tract, NSAIDs are invariably administered after meals or, generally, when the stomach is not empty. This pharmacological principle is confirmed by the recommendations found in the labeling of these medications. Patients who have an ulcer or who are susceptible to developing ulcers are commonly advised to avoid taking NSAIDs for pain, inflammation, and/or fever.
Other measures which can be taken to decrease GI side affects associated with NSAID therapy is to coadminister an H2 blocker e.g. ranitidine, or a prostaglandin analogue, e.g. misoprostol, with the NSAID. In fact, a combination tablet containing diclofenac sodium and misoprostol (Arthrotec®, Pharmacia Corp.) has had FDA approval since 1988.
There is a continuing need for analgesic medications able to provide high efficacy pain relief while reducing the possibility of undesirable effects. Non-steroidal anti-inflammatory drugs, including compounds such as ibuprofen, ketoprofen and diclofenac, have anti-inflammatory actions and are effective on pain associated with the release of prostaglandins and other mediators of inflammation. For example, diclofenac and pharmaceutically acceptable salts thereof, e.g. diclofenac sodium, are considered to be extremely potent and effective as an analgesic and anti-inflammatory agent. Diclofenac is approved in the United States for the long-term symptomatic treatment of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. It is also considered to be useful for the short-term treatment of acute musculoskeletal injury, acute shoulder pain, postoperative pain and dysmenorrhea. However, NSAIDs such as diclofenac produce side effects in about 20% of patients that require cessation of medication. Side effects include, for example, gastrointestinal bleeding and the abnormal elevation of liver enzymes.
Non-steroidal anti-inflammatory drugs (NSAIDs) exert most of their anti-inflammatory, analgesic and antipyretic activity and inhibit hormone-induced uterine contractions and certain types of cancer growth through inhibition of prostaglandin G/H synthase, also known as cyclooxygenase. Inhibition of COX-1 causes a number of side effects including inhibition of platelet aggregation associated with disorders of coagulation, and gastrointestinal side effects with the possibility of ulcerations and of hemorrhage. It is believed that the gastrointestinal side effects are due to a decrease in the biosynthesis of prostaglandins which are cytoprotective of the gastric mucosa.
A high incidence of side effects has historically been associated with chronic use of classic cyclooxygenase inhibitors, all of which are about equipotent for COX-1 or COX-2, or which are COX-1-selective. While renal toxicity occurs, it usually becomes evident in patients who already exhibit renal insufficiency (D. Kleinknecht, Sem. Nephrol. 15: 228, 1995). By far, the most prevalent and morbid toxicity is gastrointestinal. Even with relatively nontoxic drugs such as piroxicam, up to 4% of patients experience gross bleeding and ulceration (M. J. S. Langman et al, Lancet 343: 1075, 1994). In the United States, it is estimated that some 2000 patients with rheumatoid arthritis and 20,000 patients with osteoarthritis die each year due to gastrointestinal side effects related to the use of COX inhibitors. In the UK, about 30% of the annual 4000 peptic ulcer-related deaths are attributable to COX inhibitors (Scrip 2162, p.17). COX inhibitors cause gastrointestinal and renal toxicity due to the inhibition of synthesis of homeostatic prostaglandins responsible for epithelial mucus production and renal blood flow, respectively.
The second form of cyclooxygenase, COX-2, is rapidly and readily inducible by a number of agents including mitogens, endotoxins, hormones, cytokines and growth factors. It has been proposed that COX-2 is mainly responsible for the pathological effects of prostaglandins, which arise when rapid induction of COX-2 occurs in response to such agents as inflammatory agents, hormones, growth factors, and cytokines. Selective inhibitors of COX-2 have anti-inflammatory, antipyretic and analgesic properties similar to those of a conventional non-steroidal anti-inflammatory drug (NSAID), but COX-2 inhibitors have been touted as providing a reduced potential for gastrointestinal toxicity, among other side effects. Nevertheless, experience with selective COX-2 inhibitors is limited relative to experience with non-selective COX inhibitors (which non-selectively inhibit COX-1 and COX-2). Non-selective COX inhibitors are widely used, and it is expected that these drugs will continue to be widely used. Further, there has been recent suggestions that COX-2 inhibitors have serious but previously unrecognized side effects, including increased intraocular pressure and the risk of glaucoma, as well as possible effects on the central nervous system.
For years, neutralization of gastric acid with antacids was the only relief from the pain of ulcers. However, more recently, a class of antisecretory agents that do not exhibit anticholinergic or H2 histamine antagonistic properties, but that suppress gastric acid secretion by the specific inhibition of the H+, K+—ATPase enzyme system at the secretory surface of the gastric parietal cell, has been developed. These agents (hereinafter “proton pump inhibitors”) provide a more specific class of inhibitors of gastric acid secretion in mammals and man by blocking the final step of acid production.
Generally, proton pump inhibitors, their single enantiomers or alkaline salts thereof, are used for the prevention and treatment of gastric acid related diseases including, but not limited to, reflux esophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer. These proton pump inhibitors may also be used in patients in intensive care situations, in patients with acute upper gastrointestinal bleeding, pre- and postoperatively to prevent acid aspiration of gastric acid and to prevent and treat stress ulceration. Also, they may be useful in the treatment of psoriasis as well as in the treatment of Helicobacter infections and diseases related to these. Additionally, these proton pump inhibitors may be used for the treatment of other gastrointestinal disorders where gastric acid inhibitory effect is desirable, such as patients with Non Ulcer Dyspepsia, in patients with symptomatic gastro-esophageal reflux disease, in patients with gastrinomas, and in particular in patients on NSAID therapy.
U.S. Pat. No. 5,817,338 (Bergstrand, et al.) describes multiple unit tableted dosage forms of omeprazole, a proton pump inhibitor commercially available for inhibiting gastric acid secretion in humans. Therein, it is suggested that omeprazole may be used for treatment of other gastrointestinal disorders where gastric acid inhibitory effect is desirable, e.g., in patients on NSAID therapy. However, this patent does not describe pharmaceutical formulations combining a proton pump inhibitor such as omeprazole with an NSAID.